1. Field of the Invention
The present invention relates to medical compositions and methods for the chemotherapeutic treatment of lymphomas, leukemias, and leiomyomas generally and, more particularly, to compositions comprising one or more N-substituted 2(1H) pyridones and/or one or more N-substituted 3(1H) pyridones as active ingredient(s). The selected compounds may be used alone or as an adjunct to other forms of neoplastic therapy including surgery, other chemotherapeutic compounds, radiation therapy, and immunotherapeutic agents.
2. Background Art
The causes of leukemias and leiomyomas are poorly understood, are complex, and involve interplay between the basic genetic material in the nucleus of cells. An abnormal reaction of cellular generic DNA to internal or external factors can create a new deviation in the cell genetic code, or in the genetic DNA generated communication proteins which creates neoplastic perturbations in the transcription process governing the specific cell cycle stages of otherwise normal cell division, and proliferation.
Cell proliferation is defined as the increase in number of cells resulting from completion of the cell cycle, as contrast to growth, which is the increase in the individual cell mass.
Extracellular or intracellular factors can determine whether a quiescent cell will begin to proliferate and also whether a normal proliferating cell in phase G1 will begin to cycle or will revert to quiescence. After cells enter into the S phase, cell-cycle events become largely independent of prior extracellular factors., while they go on to divide and produce two daughter cells.
Among the carcinogenic factors of external origin, acting internally, are physical carcinogens such as ionizing or ultraviolet radiation, and the presence of foreign substances such as asbestos. Carcinogenic substances acting internally include various chemicals, natural or man-made, which can effect directly or indirectly cell DNA to elicit intracellular oncogenic events. In addition biological substances such as bacteria, viruses, parasites, hormones and cytokines have been implicated in mammalian carcinogenesis.
In lymphomas, leukemias and leiomyomas, the control of proliferation is deranged. After induction of altered proliferation control, deranged cell differentiation is initiated in phase G1, and is a hallmark of neoplastic cells (Pardee. A. B., Science, Nov. 3, 1989, p.603).
Neoplasms are manifest when the normal progression of the orderly relationship between cell division and cell differentiation malfunctions. With the usual cell division sequence in normal cells, the proliferation of cells is restricted to non-differentiated stem cells which ordinarily differentiate and reproduce to provide a replacement for aged dying cells.
Neoplasms arising from lympho-hematopoietic origin may be identified as leukemias, lymphomas, leiomyomas, etc.
The term "anti-neoplastic" or "anti-tumor" refers herein to the (a) chemotherapeutic inhibition or arrest of the growth, and (b) the destruction of mammalian benign, or malignant tissues such as leukemias, lymphomas, and leiomyomas found in various organs and tissues of the body.
Although most tissues and organs of the human body may become neoplastic, the basic processes leading to diverse tumors appear to be quite similar. Normal cells proliferate or reproduce in rigorous compliance with programmed guidance from parental or adjacent cells. Such unceasing, disciplined instruction ensures that each tissue maintains a size, architecture and function appropriate to the body's needs.
Neoplastic cells, in distinct contrast, become unresponsive to the usual controls of parental or adjacent cells with respect to proliferation, architecture and/or function. These neoplastic cells frequently (a) migrate from the site where they began, (b) invade nearby tissues, and (c) travel through the blood and lymphatic circulatory systems to form neoplastic lesions at distant sites in the body. These lesions become lethal when they disrupt the normal function of other tissues or organs essential for the patient survival.
Multiple genetic changes occur during the transformation of normal cells into neoplastic cells. This is facilitated in neoplastic cells by loss of fidelity in the processes that replicate, repair, and segregate the genome structure. Advances in our understanding of the cell cycle reveal how fidelity is normally achieved by the coordinated activity of cyclin-dependent kinases, checkpoint controls, and repair pathways, and how this fidelity can be abrogated by specific genetic changes. The recognition of molecular mechanisms for cellular transformation may help identify the mechanisms by which chemotherapeutic compounds are useful in the treatment of neoplastic diseases (Hartwell, L. and Kasten, M., 1994, Science, 266:1821-1828).
Control systems enforcing interdependency in the cell cycle are called "checkpoints." Elimination of checkpoints can result in cell death, infidelity in the distribution chromosomes or other cellular organelles, or increased susceptibility to external perturbations such as DNA damaging agents. Such perturbations can result in neoplastic transformation of cells and tissues (Hartwell, L. and Weinert, T., 1989, Science, 246:629-634).
The cell-type-specific expression of most genes is determined at the transcription level. Transcription factors are involved in the control of the process. To understand the basis of this regulation, it has become important to analyze the control of transcription factors themselves. A variety of transcriptional, translational, and post-translational mechanisms have been described. The most direct way for a cell to regulate the abundance of a factor is to adjust the production of the mRNA encoding it. Thus far, the control of many cell-type and tissue-specific transcription factors has been found to occur at the transcription level (Falvey, E., and Schibler, U., FASEB J., 1991, 5:309-314).
Recent studies indicate that extracellular signals often effect cell proliferation and differentiation by modulating intracellular transcription factor activity via protein phosphorylation cascades, which involves the transduction systems used to transmit information (signals) from the cell surface to the transcription machinery of the cell nucleus (Karin, M., 1992, FASEB J. 6:2581-2590).
Cell nuclear transcription factors regulate tissue and stimulus-specific gene expression through their ability to integrate extracellular signals at the nucleus. Several human diseases, including neoplasias, cardiovascular disease, and neurological and autoimmune disorders, result from aberrations in the expression of genes regulated by these transcription factors (Manning, A. Gonzales, R., and Bennett, B., Expert Opin. Ther. Pat., 1997, 7:225-231).
Normally, the body's tissues prevent excessive proliferation of cells by depriving them of excessive amounts of growth-stimulating factors, or by flooding the cells with antiproliferative factors derived from adjacent or parental cells which block the actions of the growth stimulating factors.
Certain cellular proteins, through their intrinsic ability to regulate a host of other genes involved in the control of cell proliferation, can reorganize and redirect a cell's normal or abnormal fate. Thus, the loss of these growth controlling genes by deletion or mutation is a common occurrence in neoplasias (Lozano, G. and Hulboy, D. L., Methods (San Diego) 1995, 8:215-224.)
Some cell cycle derangements stem from extracellular influences. Many neoplasia causing oncogenes, for example, turn out to encode components of the pathways through which various growth factor signals feed into the cell cycle to stimulate cell division. This is an important demonstration that the protein encoded by the p53 tumor suppresser gene inhibits cell growth by turning on the production of a specialized protein that blocks the cell cycle. The intracellular gene encoding one component of the cell cycle machinery, a protein called cyclin D1, as well as several others, are oncogene candidates. A significant amount of experimental evidence indicates that excess cyclin D1 causes neoplasias, but additional data suggest that several gene changes are implicated in the transformation of normal cells into a neoplastic configuration. For example, a hallmark of normal healthy cells is their ability to differentiate, but neoplastic cells cannot differentiate due the blockade of this response via the combined action of cyclins D2 and D3 (Marx, J., 1994, Science, 263:319-321).
Other recent data strongly suggest that deregulation of the restriction checkpoints in the cell-cycle G-1 phase is required for the transition to neoplastic disarray as seen in neoplasias (Strauss, M.; Lucas, J.; Bartek, J. Nat. Med. (N.Y.), 1995 1:1245-1246).
Mitogenic stimulation of normal cells initiates a sequence of events leading to activation of cyclin-dependent kinases, phosphorylation of Rb, and subsequent entry into of the cell into the S phase. Many types of neoplasms have lost sensitivity to the growth-inhibitory actions of TGF-beta-1, and this may derive from dysregulated expression of cyclin, cdk, and cdk inhibitor genes (Satterwhite, D. and Moses, H., 1994-1995 (Publ. 1995), Invasion Metastasis, 14:309-318).
Large T-antigen expression in human fibroblasts selectively uncouples cyclin D1 from cdk4, and subsequent immortalization of these cells results in additional changes in the cyclin D-dependent cell cycle regulatory pathways (Peterson, S. et al., 1995, Cancer Res., 55:4651-4657).
Representative Neoplasms of the Immune System
Each neoplasm of the immune system exhibits a distinct clinical and pathologic character, yet these disorders share a number of common features. Systemic symptoms of fever, night sweats, and weight loss may be present and are associated with advanced stages of the disease. These tumors usually appear in one or more organs of the hematopoietic system (lymph nodes, spleen, liver, bone marrow). If untreated, fatal dissemination to all of these organs, as well as other sites occurs.
Chronic myeloid leukemia (CML) usually presents clinically in a chronic phase of variable duration, after which a fatal condition similar to acute leukemia (blast crisis) develops. The problem of initial therapy for chronic phase CML is that current conventional therapy offers little chance of long-term survival of the patient with no chance of cure, whereas an agent that offers superior survival and a chance of cure is very toxic and expensive (Kattan, M., et al., Ann. Intern. Med., 1996; 125:541-548).
The disease is characterized by overproduction of granulocytic cells (especially neutrophilic types), leading to marked splenomegaly, and very high white blood cell counts. Rises in basophils and thrombocytosis occur frequently.
Inhibition of proliferation by pirfenidone of human uterine leiomyomas or fibroid cells in vitro. According to the literature, leiomyomas are the most common pelvic tumors in women with a reported incidence of 20% or more (Merrill, J., Creasman. W. 1990, "Danforth's Obstetrics and Gynecology," Scott, J., et al., eds., 6th edition. Philadelphia. Lippincott. pp. 1023-1039). Most common symptoms associated with these benign tumors are excessive abnormal uterine bleeding, pelvic pain, infertility and increased urinary frequency. Consequently, the presence of leiomyomas is the leading cause for hysterectomy in the United States (Wilcox, L. et al., 1994, Hystersectomy in the United States, 1990, Obstet. Gynecol. 83:549-555).
The majority of chemotherapeutic neoplasia agents in current clinical practice are toxic compounds and exert their greatest anti-neoplasia effect when employed at the maximum tolerated dose. With these chemotherapeutic agents, toxic actions to normal tissue can greatly limit the amount that can be safely administered. To date, the most commonly utilized agents are only partially selective in their toxicity. Thus, they are damaging to both normal and neoplastic cells. These agents disrupt major intracellular systems such as DNA synthesis and essential enzymes systems. Nevertheless treatment of neoplastic disease is predicated on exploiting the small differences between healthy normal cells and neoplastic cells.
Accordingly, it is a principal object of the present invention to provide compositions for the inhibition or arrest of the growth or for the destruction of mammalian benign and malignant tumors lymphomas, leiomyomas, and leukemias.
It is a further object of the present invention to provide such compositions that provide a means of (1) arresting the proliferation of and (2) then killing the abnormal cells of neoplastic tissue without serious or fatal injury to healthy normal cells and tissues.
It is an additional object of the invention to provide such compositions that comprise one or more N-substituted 1-(1H) pyridone(s) and/or N-substituted 3-(1H) pyridone(s) as active anti-tumor ingredient(s).
Other objects of the present invention, as well as particular features and advantages thereof, will be elucidated in, or be apparent from, the following descriptions.